Marijuana has been used for recreational and medicinal purposes for centuries. The wide appeal of this drug lies in its ability to alter mood and behavior. The therapeutic effects of marijuana are surprisingly broad and include its ability to act as an antiemetic, antiinflammatory, antiglaucoma, analgesic, and appetite enhancing agent. These diverse physiological effects are mediated by the active principal in marijuana, (-)-9-tetrahydrocannabinol (THC), for which specific receptors were first identified in brain. Only two subtypes of cannabinoid receptors, CB1 and CB2, have been identified, cloned, and sequenced to date and have been found to be members of the superfamily of G-protein coupled receptors. The discovery of brain receptors for THC led to the more recent discovery of the endogenous cannabinoid agonist anandamide, and other potential cannabimimetic fatty acid amides. Previous efforts in my lab have led to an understanding of the basic signaling mechanisms of both CB1 and CB2 receptors. We have developed a selective antagonist for the CB1 receptor and are attempting to develop CB2 selective agonists and antagonists which are currently unavailable. We have discovered several new members of the fatty acid ethanolamide family, some with cannabinoid agonist activity. In collaboration with Sandy Markey's lab, we have developed a GC/MS method to measure fatty acid ethanolamides that is both specific and sensitive and have begun mapping the levels of these compounds in rat brain and periphery and in normal and diseased human samples. Our preliminary results indicate that anandamide and related fatty acid ethanolamides are under the regulation of important brain receptors such as GABA, glutamate, and dopamine receptors and that this compound is widely distributed in the brain and periphery in both humans and rats. We are currently testing the hypothesis that anandamide represents a novel neurotransmitter which is not stored in synaptic vesicles due to its hydrophobic nature, but is synthesized on demand to act as a transynaptaic, parasynapatic, or autocoid agonist for the CB1 and potentially other currently unknown receptors.